The applicant is an Associate Professor of Medicine in the Division of Infectious Diseases, an Associate Professor of Epidemiology in the Department of Biostatistics and Epidemiology, and a Senior Scholar at the Center for Clinical Epidemiology and Biostatistics at the University of Pennsylvania School of Medicine. He is an established clinical investigator with an extensive track record as the Principal Investigator of peer- reviewed federal funding. The candidate has developed a highly successful and innovative patient-oriented research program focusing on the epidemiology of antimicrobial resistance. He also has a clear record of accomplishment and commitment to mentoring the next generation of patient-oriented researchers. He has played a critical role in building clinical research training opportunities through expansion of research training programs, course development and instruction, and individual mentoring. The University of Pennsylvania is committed to providing the applicant with a strong environment for patient-oriented research and mentoring, including multiple institutional training grants, an institutional Clinical and Translational Science Award (CTSA) program, an extraordinarily successful Master of Science in Clinical Epidemiology (MSCE) training program, and outstanding laboratory, biostatistics, and data management support. One of the applicant's current R01s is a prospective cohort study examining the epidemiology of gastrointestinal tract colonization with fluoroquinolone-resistant Escherichia coli (FQREC) in long-term care facility (LTCF) residents. While this study focuses on several critical steps in the ultimate development of clinical FQREC infection, the earliest aspects of this pathway of colonization (i.e., the progression of an E. constrain from FQ-susceptible to FQ-resistant) remain unstudied. Elucidation of these earlier steps in the evolution of FQ resistance is critical in identifying key patient variables (e.g., antibiotic use) and organism variables (e.g., virulence factors) which may be amenable to intervention. Indeed, this application represents a powerful human model for studying evolution of antibiotic resistance in the clinical setting. With its established infrastructure and unique longitudinal patient cohort, the ongoing LTCF R01 study provides a distinctive opportunity to answer the important new questions proposed in this application. Furthermore, the new proposed research will expand considerably the scope of the ongoing LTCF R01. This unique research infrastructure will also offer valuable research and mentoring opportunities for the applicant's trainees. Support from the K24 will allow the candidate to substantially expand his research program and considerable track record of successful individual mentoring in patient-oriented research focused on antimicrobial resistance. RELEVANCE (See instructions): Dramatic increases in antimicrobial resistance threaten our most commonly used antibiotics. The research proposed in this application will advance our understanding of the forces driving resistance, thereby identifying strategies to curb further emergence of resistance. Support from a K24 award will provide Dr. Lautenbach with sufficient time to expand his research program and build on his considerable track record of successful mentoring in patient-oriented research focused on antimicrobial resistance.